The human lung is composed of a large number of small air sacs, called alveoli, in which gases are exchanged between the blood and the air spaces of the lungs. In healthy individuals, this exchange is mediated by the presence of a protein-containing surfactant complex that prevents the lungs from collapsing at the end of expiration.
Lung surfactant complex is composed primarily of lipids and contains minor amounts of various proteins. An absence of adequate levels of this complex results in malfunction of the lung. This syndrome is called Respiratory Distress Syndrome (RDS) and is the single most important cause of morbidity and mortality in pre-term infants.
RDS is mainly treated with replacement therapy whereby exogenous pulmonary surfactant preparations extracted from animal lungs, known as modified natural surfactants are administered to the human in need. For instance, modified natural surfactants used in the clinical practice are poractant alfa derived from porcine lung, and sold under the trademark of Curosurf®, beractant (Surfacten® or Survanta®) bovactant (Alveofact®), both derived from bovine lung, and calfactant derived form calf lung (Infasurf®).
Synthetic surfactants mimicking the composition of the modified natural surfactants, and known as reconstituted surfactants, have also been developed.
Exogenous pulmonary surfactants are currently administered by endotracheal instillation as suspension in a saline aqueous solution to intubated pre-term infants kept under intermittent positive pressure ventilation (IPPV). However, IPPV is in itself an invasive procedure which frequently requires supplemental medication like treatment with sedatives, analgesic agents and catecholamines.
Furthermore IPPV in pre-term infants with RDS has long been recognized to contribute to lung injury which may lead to the development of pneumothorax and/or bronchopulmonary dysplasia (BDP); and may cause reduction of mucociliary clearance, mucosal injury, and secondary infections as well as blockage of the endotracheal.
In view of the potential complications associated with intubation and mechanical ventilation, attention has been focused on different approaches of administration of exogenous surfactant.
Since long time, as a possible initial respiratory support for very low birth weight (VLBW) infants, use of early nasal Continuous Positive Airway Pressure (nCPAP), that delivers air into the lungs through specially designed nasal devices such as masks, prongs or tubes, has been introduced in neonatal intensive care.
Recently, to give exogenous surfactant without mechanical ventilation, the use of a thin gastric tube placed in the trachea supported with nCPAP has been proposed (Gopel W et al, abstract presented at the 20th International Workshop on Surfactant Replacement, Belfast, Jun. 2-5, 2005, page 12: Kribs, A et al. Paediatr Anaesth. 2007 April; 17(4):364-9.).
In particular, Gopel W and colleagues reported on the administration of 60 mg bovine surfactant, diluted to 30 mg/ml, by a 5 Fr gastric tube in spontaneously breathing infants with a mean weight of about 1 kg.
However, to improve the clinical outcome, an initial dose higher than 60 mg/kg body weight, is currently recommended. A dose higher than 60 mg/kg requires a higher concentration of the surfactant preparation to be used, in particular of at least 40 mg/ml.
Since viscosity increases with surfactant concentration, the administration of a concentration of at least 40 mg/ml, by means of a gastric tube that has a very small diameter (5 Fr. corresponds to about 1.7 mm) would be only possible with a surfactant having low viscosity. In fact high viscosities would make the passage of the surfactant through the gastric tube and the small airways more difficult and may therefore result in uneven distribution in the lungs of the pre-term infants. Theoretically, surfactants having high viscosities carry the risk of blockage of the gastric tube and of acute airway obstruction.
In view of the drawbacks of the methods previously used for delivery of exogenous surfactant, alternative therapeutic methods for surfactant administration are needed. Such methods should provide at least identical or, preferably improved clinical outcome without the potential complications associated to endotracheal intubation and mechanical ventilation.
The therapeutic methods and kits disclosed herein provide a real improvement over therapies described in the art.